EP4340847A1 - Composition of mesalazine enteric tablet formulation - Google Patents

Composition of mesalazine enteric tablet formulation

Info

Publication number
EP4340847A1
EP4340847A1 EP21940969.5A EP21940969A EP4340847A1 EP 4340847 A1 EP4340847 A1 EP 4340847A1 EP 21940969 A EP21940969 A EP 21940969A EP 4340847 A1 EP4340847 A1 EP 4340847A1
Authority
EP
European Patent Office
Prior art keywords
enteric
mesalazine
tablet
poly
methyl methacrylate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21940969.5A
Other languages
German (de)
French (fr)
Inventor
Hatice ONCEL
Onur Pinarbasli
Feristah BILGIN
Hande GAYRETLI
Nurdan ATILGAN
Asuman AYBEY DOGANAY
Nagehan SARRACOGLU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ilko Ilac Sanayi ve Ticaret AS
Original Assignee
Ilko Ilac Sanayi ve Ticaret AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ilko Ilac Sanayi ve Ticaret AS filed Critical Ilko Ilac Sanayi ve Ticaret AS
Publication of EP4340847A1 publication Critical patent/EP4340847A1/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/005—Coating of tablets or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/606—Salicylic acid; Derivatives thereof having amino groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer

Definitions

  • the present invention relates to formulate a pharmaceutical enteric tablet composition comprising mesalazine, a process for the production of said formulation with a multilayer enteric coating.
  • Mesalazine which is commonly known as 5-ASA and mesalamine, is an aminosalicylate (5-aminosalicylic acid) with anti-inflammatory properties. It is indicated for the induction of remission in patients with active, mild-to-moderate ulcerative colitis and for the maintenance of remission of ulcerative colitis. Its chemical name is 5- amino-2-hydroxybenzoic acid with a molecular formula C 7 H 7 N0 3 .
  • Mesalazine is slightly soluble in water, very slightly soluble in methanol and practically insoluble in chloroform; soluble in diluted HCI and diluted alkali hydroxides.
  • IBD Inflammatory bowel disease
  • Ulcerative colitis is a chronic inflammatory bowel disease affecting only the colon and shows a continuous distribution in the gastrointestinal mucosa. In most patients mainly the distal part of the colon and the rectum are inflamed with often a proximal spread.
  • Enteric coatings have been used for many years to arrest the release of the drug from orally ingestible dosage forms. Depending upon the composition and/or thickness, the enteric coatings are resistant for required periods of time before delivery of the therapeutic agents to the lower part of the gastrointestinal track, especially the large intestine or the colon.
  • Salofalk® Magneticensaftresistente Tabletten, 500 mg & 250 mg; Dr. Falk Pharma GmbH
  • Salofalk® is a known enteric coated tablet, available on the market.
  • Salofalk® was selected as reference product. It is comprised of a core with an enteric coating, where the enteric coating is a polyacrylic ether.
  • Salofalk® is a tablet comprised of mesalazine, butylated methacrylate copolymer, calcium stearate, croscarmellose sodium, iron oxide, glycine, silicon dioxide, hypromellose, macrogol 6000, methacrylic acid: methyl methacrylate copolymer (1:1), microcrystalline cellulose, sodium carbonate, povidone k25, Talc, titanium dioxide.
  • the main site of action of Salofalk® is said to be the terminal ileum and the ascending colon.
  • US4540685 relates to a process for the production of readily soluble pharmaceutical preparations based on 5-aminosalicylic acid.
  • This invention is particularly suitable for the production of tablets, dragee cores or capsules containing from 200 mg to 900 mg of 5 aminosalicylic acid per pharmaceutical formulation unit.
  • These forms of administration have film coatings based on polymeric substances with pH related solubility properties.
  • EP1453487 discloses pharmaceutical mesalazine dosage form with multiple coatings comprising therapeutic agents with improved resistance to coating fractures during processing, manufacturing or packaging.
  • EP2611429 discloses pharmaceutical mesalazine enteric coated tablet having at least an intermediate layer and enteric coating where the tablet core hardness is controlled to be comprised between 80 N and 105 N and the intermediate layer represents less than 2% by weight of the tablet.
  • high dose formulations comprising 500 mg to 10 gram mesalazine as capsule, tablet or sachet forms (EP0977557, W02004/093884, EP2621477,
  • the present invention relates to produce mesalazine enteric coated tablet maintaining specific in-vitro dissolution to provide desired site of delivery of therapeutically effective amount of therapeutic agents in the gastrointestinal track. Delivery directly in the colon requires formulations which are capable of passing over the entire track of the small intestine, including the duodenum, jejenum, and ileum, so that the active ingredients are released directly in the colon.
  • Mesalazine is a locally acting drug and is destroyed by stomach acids as a result of direct oral use, which preventing its performance in the required area.
  • a stable mesalazine enteric coated tablet formulation has been developed to ensure proper in-vitro release initially and during storage conditions especially for whose local release is affected by conditions such as temperature and humidity.
  • a stable pharmaceutical mesalazine enteric tablet formulation the produced enteric tablet releases less than 1% of the labeled amount of mesalazine after 2 hours acid stage when measured using USP dissolution apparatus II (paddle), 100rpm, 500 ml_ of 0.1 N hydrochloric acid medium and less than 1% of the labeled amount of mesalazine after 1 hour buffer stage 1 when measured using USP dissolution apparatus II (paddle), 100 rpm, 900 ml_ of pH 6.0 phosphate buffer, wherein the core tablet contains multilayer enteric coating consisting of;
  • the first enteric coating layer comprises basic butylated methacrylate copolymer with a ratio range of 20:1 to 65:1 active ingredient mesalazine to basic butylated methacrylate copolymer,
  • the second enteric coating layer covering the first enteric coating layer comprises mixture of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1.
  • the second enteric coating layer covering the first enteric coating layer comprises mixture of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1 in a ratio of 1:2 to 1:4.
  • the second enteric coating layer covering the first enteric coating layer comprises mixture of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1 in a ratio of 1:4.
  • the core tablets present in the enteric tablet formulation are prepared by wet granulation.
  • the tablet formulation comprises 500 mg mesalazine.
  • the tablet formulation comprises 250 mg mesalazine.
  • a stable mesalazine enteric coated tablet maintaining the desired site of delivery of the therapeutically effective amount of active ingredient is provided by the present invention with providing more specific and reliable release of mesalazine than reference product (Salofalk®) to the lower part of the gastrointestinal tract, especially to the colon.
  • reference product Siofalk®
  • the tablets of the invention contain a core tablet, an intermediate layer, and multilayer enteric coatings superimposed on it.
  • the first enteric coating layer comprises basic butylated methacrylate copolymer. It is the protective coating layer for providing durability of the tablet under stability conditions especially humidity condition.
  • the second enteric coating layer comprises mixture of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1.
  • the present invention provides a method for preparing a mesalazine enteric coated tablet comprising:
  • the mesalazine granulates are produced by granulating active substance with microcrystalline cellulose, povidone, croscarmellose sodium and glycine.
  • the unit dosage form is a compressed spherical or elliptical tablet.
  • the tablet is comprised of a solid form of therapeutically active agent mesalazine and is compressed using conventional equipment and processes.
  • terapéuticaally effective amount refers to an amount, which achieves a desired effect, when administered to a living subject.
  • a dosage form is required which, after oral administration, enables the local availability of the active ingredient mesalazine in a sufficiently high concentration at the site of inflammation.
  • active ingredient or “active pharmaceutical ingredient” means any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals.
  • the active ingredient is mesalazine or its pharmaceutically acceptable salts, esters, and solvates thereof.
  • the enteric tablet composition is provided in a unit dose formulation comprising 500 mg and 250 mg mesalazine.
  • 'stable' as used herein means the enteric tablet release the therapeutically effective amounts of active ingredient mesalazine into specific delivery region after production (To, initially) and during the storage conditons throughout the shelf life. Especially the products entail USP performance tests for Mesalamine Delayed Release Tablets.
  • the proposed USP tests for enteric tablets requires that the product withstand agitation (paddle at 100 rpm) in the artificial gastric fluid (0.1 N hydrochloric acid) at 37°C ⁇ 0.5°C, releasing less than 1% of the labeled amount of mesalazine for 2 hours and also the product withstand agitation (paddle at 100 rpm) in the pH 6.0 phosphate buffer at 37°C., releasing less than 1% of the labeled amount of mesalazine for 1 hour, while dissolving not less than 80% (Q) of the labeled amount of mesalazine in 90 minutes at 37°C with a buffer of pH 7.2. This is also considered as dissolution stability as well.
  • the stability of the products can be determined by in-vitro dissolution studies of real time studies or during storage conditions.
  • compositions of this invention also generally comprise pharmaceutically acceptable excipients.
  • excipient means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a subject. Excipients may act to facilitate incorporation of the therapeutically active agent into the dosage form, modify the release of the therapeutically active agent from the dosage form, stabilize the therapeutically active agent, or enhance absorption of the therapeutically active agent.
  • the enteric coating solution used to form the enteric coating layer on the tablets will comprise a water soluble or water dispersible film forming enteric polymer dissolved or dispersed in an aqueous vehicle.
  • a number of such film forming enteric polymers are known in the prior art which will serve the present purposes. These will have conventional solubility characteristics of enteric polymers i.e. they will be insoluble in acid but will be soluble in a neutral-to-nearly alkaline medium.
  • the polymeric coating layer comprises a hydrophilic gelling polymer or copolymer that swells on contact with gastro-intestinal juices to form a film surrounding the core.
  • the swellable polymeric coating layer which surrounds the core protects the integrity of the core and prevents the release of mesalazine during the transit in the small intestine.
  • the swellable polymeric coating layer may be comprised of any suitable hydrophilic gelling polymer known to those skilled in the art.
  • suitable hydrophilic gelling polymers include but are not limited to cellulose polymers such as methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydro xyethylcellulose, hydroxypropylmethylcellulose, and the like, vinyl polymers such as polyvinylpyrrolidone, poly vinyl alcohol, and the like, acrylic polymers and copolymers such as acrylic acid polymer, methyacrylic acid copolymers, ethyl acrylate-methyl methacrylate copolymers, and the like; natural or synthetic rubbers, poloxamers, polysaccharides, and mixtures thereof.
  • multilayer enteric coating comprises basic butylated methacrylate copolymer, poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1.
  • a first enteric coating layer is applied onto the film coated tablet core with a solution comprising basic butylated methacrylate copolymer (lUPAC name: Poly(butyl methacrylate-co-(2-demethylaminoeethyl) methacrylate-co-methyl methacrylate) 1:2:1).
  • Basic butylated methacrylate copolymer is commonly known as Eudragit® E.
  • Eudragit® E is a copolymer of 2-(dimethylamino)ethyl methacrylate, butyl methacrylate and methyl methacrylate having a mean relative molecular mass of about 150.000.
  • the ratio of 2-(dimethylamino)ethyl methacrylate groups to butyl methacrylate and methyl methacrylate groups is about 2:1:1.
  • Synonyms of basic butylated methacrylate copolymer are amino methacrylate copolymer; aminoalkyl methacrylate copolymer E; butyl methacrylate, dimethylaminoethyl methacrylate, methyl methacrylate polymer; butyl methacrylate, methyl methacrylate, dimethylaminoethyl methacrylate polymer. It has reliable moisture protection and soluble in gastric juice up to pH 5.0, swellable and permeable above pH 5.0.
  • a second enteric coating layer is applied onto the tablet having one enteric coating layer with a solution comprising mixture of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1 in a ratio of 1:2 to 1:4.
  • Poly(methacrylic acid, methyl methacrylate) 1:2 is commonly known as Eudragit® S.
  • Eudragit® S is an anionic copolymer derived from methacrylic acid and methyl methacrylate, with a ratio of free carboxyl groups to the ester groups of approximately 1:2, and a mean molecular weight of approximately 135,000. It has effective and stable enteric coatings with a fast dissolution in the upper Bowel.
  • Eudragit® L Poly(methacrylic acid, methyl methacrylate) 1:1 is commonly known as Eudragit® L.
  • Eudragit® L is an anionic copolymer derived from methacrylic acid and methyl methacrylate, with a ratio of free carboxyl groups to the ester groups of approximately 1:1, and a mean molecular weight of approximately 135,000. It has effective and stable enteric coatings with a fast dissolution in the upper Bowel and site specific drug delivery in intestine by combination with EUDRAGIT S grades.
  • the coating solutions preferably contain a plasticizer.
  • the plasticizer may be a solid plasticizer, a liquid plasticizer, or a combination thereof.
  • the solid plasticizers include polyethylene glycol 3350, polyethylene glycol 4000, polyethylene glycol 8000, or Pluronic F86.
  • the liquid plasticizer include triethyl citrate, glyceryl triacetate, acetyltriethylcitrate, dibutyl sebacate, diethyl phthalate, polyethylene glycol 400, glycerol, castor oil, or mixtures thereof. These plasticizers are present in an amount to facilitate the coating process and to obtain an even coating film with enhanced physical stability. In this present invention, triethyl citrate is preferred.
  • the coating material may also comprise inert solid particulates.
  • preferred inert solid particulates include talc and titanium dioxide.
  • Enteric polymers are generally applied onto the unit dosage forms as solutions in organic or aqueous solvents.
  • the solvents commonly employed as vehicles are water, methylene chloride, ethanol, methanol, isopropyl alcohol, acetone, ethyl acetate and combinations thereof.
  • the choice of the solvent is based primarily on the solubility of the polymer, ease of evaporation, and viscosity of the solution. In this present invention, mixture of water and isopropyl alcohol is preferred.
  • excipients like binder, disintegrant, lubricant, surfactants, antifoaming agents, solubilizing agents, coloring agents etc.
  • Lubricant is selected from the one of stearic acid, glycerol, palmitate stearate, magnesium stearate, calcium stearate, talc, micropowder silica gel, hydrogenated vegetable oil, sodium lauryl sulphate.
  • calcium stearate is used.
  • a wet granulation of mesalazine active ingredient and excipients of microcrystalline cellulose, povidone, croscarmellose sodium and glycine, is prepared.
  • the wet granules obtained are passed through a suitable sieve.
  • the drying process is carried out in Fluid Bed Dryer.
  • the required amount of sodium carbonate, colloidal silicon dioxide and calcium stearate are added to the granules obtained as a result of dry grinding and mixed.
  • the blend is compressed into tablets to prepare tablet cores.
  • FT03 6% 200 mg/tablet were observed with the reference product. Appearance, dissolution studies and stability analyzes were considered in the evaluations made in the product development studies of the enteric coating stage.
  • the coatings of the tablets should be uniform; the coating thickness should be evenly distributed over the tablet surface. Because homogeneous coating of qualified coatings such as enteric coating, controlled release coating in oval tablets is important in order to open the tablet at the desired pH. Likewise, attention should be paid to the uniformity of the round tablets in the coating process and to obtain the same thickness of coating all over the tablet.
  • opadry containing coating with hypromellose and polyethylene glycol was coated on the tablet core so that the tablet surface was smooth and the enteric coating could be coated homogeneously on this surface. Coating can be achieved by using fluidized bed equipment and the solid unit dosage forms are coated by continuous spray methods. The film coating layer is applied onto the tablet cores with opadry containing solution.
  • the main purpose of using basic butylated methacrylate copolymer in the formulation is to prevent exposure to moisture during the stability of the core tablet, which is very suitable for moisture absorption.
  • the main scope of using mixture of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1 is to to protect the tablet at pH values below 6 by allowing it to be released at pH values above pH 6.
  • a first enteric coating layer is applied onto the film coated tablet core with a solution comprising basic butylated methacrylate copolymer, talc, triethyl citrate and isopropyl alcohol.
  • a second enteric coating layer is applied onto the tablet having one enteric coating layer with a solution comprising mixture of poly(methacrylic acid, methyl methacrylate) 1:2 (A) and poly(methacrylic acid, methyl methacrylate) 1:1 (B), talc, triethyl citrate, yellow iron oxide, titanium dioxide and isopropyl alcohol.
  • the rate of enteric coating polymers (A and B) was changed and the results were evaluated (FT04 - FT09).
  • the final tablets are cured for 1 hour at 40-45°C.
  • Example 2 In-Vitro Dissolution Studies
  • the finished mesalazine enteric coated tablets of present invention were compared with reference product Salofalk® to evaluate their performance in the USP Mesalamine Delayed Release Tablet - Performance tests.
  • Buffer Stage 1** 900 mL of pH 6.0 phosphate buffer 100 rpm, 37°C ⁇ 0.5 °C, 1 hour Specification: Lower than 1% of the labeled amount of mesalazine dissolved
  • Buffer Stage 2 900 mL of pH 7.2 phosphate buffer
  • the content of the percentage of mesalazine (C7H7NO 3 ) released in the test medium was determined by comparing the UV maximum absorbance at 302 nm for acid stage, at 330 nm for buffer stage 1 and at 332 nm for buffer stage 2.
  • the proposed USP tests for enteric tablets requires that the product withstand agitation (paddle at 100 rpm) in the artificial gastric fluid (0.1 N hydrochloric acid) at 37°C ⁇ 0.5°C, releasing less than 1% of the labeled amount of mesalazine for 2 hours and also the product withstand agitation (paddle at 100 rpm) in the pH 6.0 phosphate buffer at 37°C., releasing less than 1% of the labeled amount of mesalazine for 1 hour, while dissolving not less than 80% (Q) of the labeled amount of mesalazine in 90 minutes at 37°C with a buffer of pH 7.2.
  • the artificial gastric fluid 0.1 N hydrochloric acid
  • the first enteric coating was applied with a solution comprising basic butylated methacrylate copolymer into the obtained film coated tablet core.
  • 2%, 3% and 5% enteric coating studies were applied for analyzing the first enteric coating layer.
  • enteric coated tablets containing dose proportional 500 mg and 250 mg mesalazine were prepared with the final formula (FT07) obtained at the end of the above-mentioned formulation determination studies.
  • the finished mesalazine enteric coated tablets of present invention (500mg and 250 mg) were compared with reference product Salofalk® (500mg and 250 mg) to evaluate their in vitro dissolution profiles provided in the USP Mesalamine Delayed Release Tablet performance test. Comparative dissolution tests were conducted based on the general dissolution test method. Dissolution testing measures the portion (%) of mesalazine that have been dissolved in the dissolution medium. Dissolution test was performed with USP Apparatus-ll (paddle) at acid stage and buffer stage.
  • Acid stage is 500 ml_ of 0.1 N hydrochloric acid and 100 rpm for 2 hours.
  • Buffer stage consists of two stages.
  • Buffer stage 1 is 900 ml_ of pH 6.0 phosphate buffer and 100 rpm for 1 hour.
  • Buffer stage 2 is 900 ml_ of pH 7.2 phosphate buffer and 50 rpm for 90 minutes. After 2 hours of acid stage, samples are taken for analysis and the tablets are taken from the medium in order and added to the medium prepared for Buffer stage 1 and proceed immediately to Buffer stage 1.
  • the percentage of labeled amount of mesalazine dissolved in acid stage and buffer stage 1 mediums should not exceed 1% at the end of the two hours.
  • the percentage of labelled amount of mesalazine dissolved should be not less than 80% (Q) (USP, Mesalamine Delayed-Release Tablets, Performance Tests). This also provides release the active substance mesalazine selectively at the inflamed areas in the gastrointestinal tract.
  • Salofalk® 250 mg Enteric Coated Tablet L19010A, Dr.
  • Salofalk® 250 mg Enteric Coated Tablet (L19010A, Dr. Falk Pharma GmbH)
  • enteric coated tablets comprising mesalazine require a defined release profile of mesalazine from the dosage form. Since the criterion for stability of an enteric coated dosage form is that it should not release a significant amount of the active ingredient in the stomach, but should dissolve completely in the higher pH environment of the intestine, in vitro dissolution stability is monitored in 0.1 N hydrochloric acid, pH 6.0 phosphate buffer and pH 7.2 phosphate buffer. The USP standards for enteric coated tablets entails stability testing of the products at elevated temperatures for extended periods of time.
  • enteric tablets coated with multilayer enteric coating polymers prepared as per the Example 1 were packed in PVC/PVDC-ALU blisters and and kept for stability testing together with reference products (Salofalk® 500mg and 250mg Enteric Coated Tablets) under conditions given as 40°C/75% relative humidity for 6 months and 25°C/60% relative humidity for 12 months duration.
  • the products were tested for content, purity and dissolution of mesalazine from enteric- coated tablets at acid and buffer medium conditions in regular intervals. Determination of content and purity was performed with a validated HPLC method at 254 nm. The determination of mesalazine release from enteric coated tablets was performed with a validated UV method at 302 nm for acid stage, at 330 nm for buffer stage 1 and at 332 nm for buffer stage 2.
  • Buffer Stage 1 900 mL of pH 6.0 phosphate buffer 100 rpm, 37°C ⁇ 0.5 °C, 1 hour
  • Buffer Stage 2 900 mL of pH 7.2 phosphate buffer 50 rpm, 37°C ⁇ 0.5 °C, 90 minutes

Abstract

A formulation of a pharmaceutical enteric tablet composition comprising mesalazine, a process for the production of said formulation with a multilayer enteric coating that provides required in-vitro dissolution profiles showing the specific delivery of the active substance contained in the dosage form to the colon initially and during storage under stability conditions.

Description

COMPOSITION OF MESALAZINE ENTERIC TABLET FORMULATION Technical field:
The present invention relates to formulate a pharmaceutical enteric tablet composition comprising mesalazine, a process for the production of said formulation with a multilayer enteric coating.
Prior Art: Mesalazine, which is commonly known as 5-ASA and mesalamine, is an aminosalicylate (5-aminosalicylic acid) with anti-inflammatory properties. It is indicated for the induction of remission in patients with active, mild-to-moderate ulcerative colitis and for the maintenance of remission of ulcerative colitis. Its chemical name is 5- amino-2-hydroxybenzoic acid with a molecular formula C7H7N03. Mesalazine is slightly soluble in water, very slightly soluble in methanol and practically insoluble in chloroform; soluble in diluted HCI and diluted alkali hydroxides.
Inflammatory bowel disease (IBD) is a term for two conditions (Crohn’s disease and ulcerative colitis) that are characterized by chronic inflammation of the gastrointestinal (Gl) tract. Prolonged inflammation results in damage to the Gl tract. Ulcerative colitis is a chronic inflammatory bowel disease affecting only the colon and shows a continuous distribution in the gastrointestinal mucosa. In most patients mainly the distal part of the colon and the rectum are inflamed with often a proximal spread.
Mesalazine plays an important role in the treatment of Crohn’s disease and ulcerative colitis by inducing and maintaining remission in chronic inflammatory bowel diseases. Its main principle of action is a topical effect at the inflamed mucosa. Systemic absorption should be minimized, as this leads to unwanted systemic side-effects and inefficient redistribution of the mesalazine to the sites of inflammation. Therefore, oral mesalazine dosage forms should release the active substance selectively at the inflamed areas in the gastrointestinal tract. When mesalazine is administered orally, a large amount of the drug is absorbed from the upper gastrointestinal tract, causing systemic side effects. Thus, the treatment of ulcerative colitis with mesalazine requires the specific delivery of the drug in the colon. Enteric coating systems are the most commonly used for colonic drug delivery, due to the pH difference between small intestine and colon.
Enteric coatings have been used for many years to arrest the release of the drug from orally ingestible dosage forms. Depending upon the composition and/or thickness, the enteric coatings are resistant for required periods of time before delivery of the therapeutic agents to the lower part of the gastrointestinal track, especially the large intestine or the colon.
Salofalk® (Magensaftresistente Tabletten, 500 mg & 250 mg; Dr. Falk Pharma GmbH) is a known enteric coated tablet, available on the market. In this study, Salofalk® was selected as reference product. It is comprised of a core with an enteric coating, where the enteric coating is a polyacrylic ether. Salofalk® is a tablet comprised of mesalazine, butylated methacrylate copolymer, calcium stearate, croscarmellose sodium, iron oxide, glycine, silicon dioxide, hypromellose, macrogol 6000, methacrylic acid: methyl methacrylate copolymer (1:1), microcrystalline cellulose, sodium carbonate, povidone k25, Talc, titanium dioxide. According to the Summary of Product Characteristics, the main site of action of Salofalk® is said to be the terminal ileum and the ascending colon.
US4540685 relates to a process for the production of readily soluble pharmaceutical preparations based on 5-aminosalicylic acid. This invention is particularly suitable for the production of tablets, dragee cores or capsules containing from 200 mg to 900 mg of 5 aminosalicylic acid per pharmaceutical formulation unit. These forms of administration have film coatings based on polymeric substances with pH related solubility properties.
EP1453487 discloses pharmaceutical mesalazine dosage form with multiple coatings comprising therapeutic agents with improved resistance to coating fractures during processing, manufacturing or packaging.
EP2611429 discloses pharmaceutical mesalazine enteric coated tablet having at least an intermediate layer and enteric coating where the tablet core hardness is controlled to be comprised between 80 N and 105 N and the intermediate layer represents less than 2% by weight of the tablet. There are also high dose formulations comprising 500 mg to 10 gram mesalazine as capsule, tablet or sachet forms (EP0977557, W02004/093884, EP2621477,
WO2011/045775).
However, there is no prior art references dealing with problems about specific delivery of active substance to the colon initially and during storage under stability conditions especially for 500 mg and 250 mg doses. The problems have been suggested that cracks in the coating may occur during storage conditions. These coating fractures may cause unreliable or inconsistent delivery or release of the therapeutic agent to the desired region of the gastrointestinal tract. Therefore there is still a need for producing enteric coated tablet comprising mesalazine stable at initially and under accelerated stability conditions. The present invention has been achieved in such circumstances.
It is an object of the present invention to produce mesalazine enteric coated tablet in order to provide specific in-vitro dissolution at after production (To) and during storage under stability conditions stable with maintaining the desired site of delivery of therapeutically effective amount of therapeutic agents in the gastrointestinal track.
Description of the Figures:
Figure 1. Release profiles of mesalazine from enteric-coated tablets performed in pH 7.2 phosphate buffer for 90 minutes with rotation at 100 rpm at 37°C followed by 0.1 N HCI and pH 6.0 phosphate buffer medium.
Description of the Invention:
The present invention relates to produce mesalazine enteric coated tablet maintaining specific in-vitro dissolution to provide desired site of delivery of therapeutically effective amount of therapeutic agents in the gastrointestinal track. Delivery directly in the colon requires formulations which are capable of passing over the entire track of the small intestine, including the duodenum, jejenum, and ileum, so that the active ingredients are released directly in the colon.
Mesalazine is a locally acting drug and is destroyed by stomach acids as a result of direct oral use, which preventing its performance in the required area. In the present invention, a stable mesalazine enteric coated tablet formulation has been developed to ensure proper in-vitro release initially and during storage conditions especially for whose local release is affected by conditions such as temperature and humidity.
According to main embodiment of the invention, there is provided a stable pharmaceutical mesalazine enteric tablet formulation, the produced enteric tablet releases less than 1% of the labeled amount of mesalazine after 2 hours acid stage when measured using USP dissolution apparatus II (paddle), 100rpm, 500 ml_ of 0.1 N hydrochloric acid medium and less than 1% of the labeled amount of mesalazine after 1 hour buffer stage 1 when measured using USP dissolution apparatus II (paddle), 100 rpm, 900 ml_ of pH 6.0 phosphate buffer, wherein the core tablet contains multilayer enteric coating consisting of;
(i) the first enteric coating layer comprises basic butylated methacrylate copolymer with a ratio range of 20:1 to 65:1 active ingredient mesalazine to basic butylated methacrylate copolymer,
(ii) the second enteric coating layer covering the first enteric coating layer comprises mixture of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1.
According to one embodiment, the second enteric coating layer covering the first enteric coating layer comprises mixture of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1 in a ratio of 1:2 to 1:4.
According to another embodiment, the second enteric coating layer covering the first enteric coating layer comprises mixture of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1 in a ratio of 1:4.
According to another embodiment, the core tablets present in the enteric tablet formulation are prepared by wet granulation.
According to one embodiment, the tablet formulation comprises 500 mg mesalazine.
According to another embodiment, the tablet formulation comprises 250 mg mesalazine.
According to one embodiment of the invention, a stable mesalazine enteric coated tablet maintaining the desired site of delivery of the therapeutically effective amount of active ingredient is provided by the present invention with providing more specific and reliable release of mesalazine than reference product (Salofalk®) to the lower part of the gastrointestinal tract, especially to the colon.
The tablets of the invention contain a core tablet, an intermediate layer, and multilayer enteric coatings superimposed on it. The first enteric coating layer comprises basic butylated methacrylate copolymer. It is the protective coating layer for providing durability of the tablet under stability conditions especially humidity condition. The second enteric coating layer comprises mixture of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1.
The present invention provides a method for preparing a mesalazine enteric coated tablet comprising:
(i) granulating a composition comprising mesalazine, a pharmaceutically acceptable salt, or ester thereof, into mesalazine granulates;
(ii) tabletting a core composition comprising the mesalazine granulates obtained in (i) to obtain a tablet core; (iii) film coating the tablet core obtained in (ii) with an intermediate layer;
(iv) a first enteric coating the coated tablet obtained in (iii) with a solution comprising basic butylated methacrylate copolymer;
(v) a second enteric coating the enteric coated tablet obtained in (iv) with a solution comprising mixture of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1.
In the present invention, the mesalazine granulates are produced by granulating active substance with microcrystalline cellulose, povidone, croscarmellose sodium and glycine.
In the present invention, the unit dosage form is a compressed spherical or elliptical tablet. The tablet is comprised of a solid form of therapeutically active agent mesalazine and is compressed using conventional equipment and processes.
The term “therapeutically effective amount” refers to an amount, which achieves a desired effect, when administered to a living subject. For the treatment of inflammatory processes and changes in the distal colon, such as ulcerative colitis, a dosage form is required which, after oral administration, enables the local availability of the active ingredient mesalazine in a sufficiently high concentration at the site of inflammation.
The term "active ingredient" or "active pharmaceutical ingredient" means any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals. In the present invention, the active ingredient is mesalazine or its pharmaceutically acceptable salts, esters, and solvates thereof. The enteric tablet composition is provided in a unit dose formulation comprising 500 mg and 250 mg mesalazine.
The term 'stable' as used herein means the enteric tablet release the therapeutically effective amounts of active ingredient mesalazine into specific delivery region after production (To, initially) and during the storage conditons throughout the shelf life. Especially the products entail USP performance tests for Mesalamine Delayed Release Tablets. The proposed USP tests for enteric tablets requires that the product withstand agitation (paddle at 100 rpm) in the artificial gastric fluid (0.1 N hydrochloric acid) at 37°C ±0.5°C, releasing less than 1% of the labeled amount of mesalazine for 2 hours and also the product withstand agitation (paddle at 100 rpm) in the pH 6.0 phosphate buffer at 37°C., releasing less than 1% of the labeled amount of mesalazine for 1 hour, while dissolving not less than 80% (Q) of the labeled amount of mesalazine in 90 minutes at 37°C with a buffer of pH 7.2. This is also considered as dissolution stability as well. The stability of the products can be determined by in-vitro dissolution studies of real time studies or during storage conditions.
In addition to the therapeutically active agent mesalazine the compositions of this invention also generally comprise pharmaceutically acceptable excipients. As used herein, "excipient" means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a subject. Excipients may act to facilitate incorporation of the therapeutically active agent into the dosage form, modify the release of the therapeutically active agent from the dosage form, stabilize the therapeutically active agent, or enhance absorption of the therapeutically active agent.
In the practice of the present invention the enteric coating solution used to form the enteric coating layer on the tablets will comprise a water soluble or water dispersible film forming enteric polymer dissolved or dispersed in an aqueous vehicle. A number of such film forming enteric polymers are known in the prior art which will serve the present purposes. These will have conventional solubility characteristics of enteric polymers i.e. they will be insoluble in acid but will be soluble in a neutral-to-nearly alkaline medium.
The polymeric coating layer comprises a hydrophilic gelling polymer or copolymer that swells on contact with gastro-intestinal juices to form a film surrounding the core. The swellable polymeric coating layer which surrounds the core protects the integrity of the core and prevents the release of mesalazine during the transit in the small intestine.
The swellable polymeric coating layer may be comprised of any suitable hydrophilic gelling polymer known to those skilled in the art. For example, suitable hydrophilic gelling polymers include but are not limited to cellulose polymers such as methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydro xyethylcellulose, hydroxypropylmethylcellulose, and the like, vinyl polymers such as polyvinylpyrrolidone, poly vinyl alcohol, and the like, acrylic polymers and copolymers such as acrylic acid polymer, methyacrylic acid copolymers, ethyl acrylate-methyl methacrylate copolymers, and the like; natural or synthetic rubbers, poloxamers, polysaccharides, and mixtures thereof. In this present invention, multilayer enteric coating comprises basic butylated methacrylate copolymer, poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1.
A first enteric coating layer is applied onto the film coated tablet core with a solution comprising basic butylated methacrylate copolymer (lUPAC name: Poly(butyl methacrylate-co-(2-demethylaminoeethyl) methacrylate-co-methyl methacrylate) 1:2:1). Basic butylated methacrylate copolymer is commonly known as Eudragit® E. Eudragit® E is a copolymer of 2-(dimethylamino)ethyl methacrylate, butyl methacrylate and methyl methacrylate having a mean relative molecular mass of about 150.000. The ratio of 2-(dimethylamino)ethyl methacrylate groups to butyl methacrylate and methyl methacrylate groups is about 2:1:1. Synonyms of basic butylated methacrylate copolymer are amino methacrylate copolymer; aminoalkyl methacrylate copolymer E; butyl methacrylate, dimethylaminoethyl methacrylate, methyl methacrylate polymer; butyl methacrylate, methyl methacrylate, dimethylaminoethyl methacrylate polymer. It has reliable moisture protection and soluble in gastric juice up to pH 5.0, swellable and permeable above pH 5.0. A second enteric coating layer is applied onto the tablet having one enteric coating layer with a solution comprising mixture of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1 in a ratio of 1:2 to 1:4. Poly(methacrylic acid, methyl methacrylate) 1:2 is commonly known as Eudragit® S. Eudragit® S is an anionic copolymer derived from methacrylic acid and methyl methacrylate, with a ratio of free carboxyl groups to the ester groups of approximately 1:2, and a mean molecular weight of approximately 135,000. It has effective and stable enteric coatings with a fast dissolution in the upper Bowel. Poly(methacrylic acid, methyl methacrylate) 1:1 is commonly known as Eudragit® L. Eudragit® L is an anionic copolymer derived from methacrylic acid and methyl methacrylate, with a ratio of free carboxyl groups to the ester groups of approximately 1:1, and a mean molecular weight of approximately 135,000. It has effective and stable enteric coatings with a fast dissolution in the upper Bowel and site specific drug delivery in intestine by combination with EUDRAGIT S grades.
In this invention, in order to increase the elasticity of the coating materials used in the invention, the coating solutions preferably contain a plasticizer. The plasticizer may be a solid plasticizer, a liquid plasticizer, or a combination thereof. The solid plasticizers include polyethylene glycol 3350, polyethylene glycol 4000, polyethylene glycol 8000, or Pluronic F86. The liquid plasticizer include triethyl citrate, glyceryl triacetate, acetyltriethylcitrate, dibutyl sebacate, diethyl phthalate, polyethylene glycol 400, glycerol, castor oil, or mixtures thereof. These plasticizers are present in an amount to facilitate the coating process and to obtain an even coating film with enhanced physical stability. In this present invention, triethyl citrate is preferred.
In addition, to facilitate the coating process, the coating material may also comprise inert solid particulates. In this present invention, preferred inert solid particulates include talc and titanium dioxide.
Enteric polymers are generally applied onto the unit dosage forms as solutions in organic or aqueous solvents. The solvents commonly employed as vehicles are water, methylene chloride, ethanol, methanol, isopropyl alcohol, acetone, ethyl acetate and combinations thereof. The choice of the solvent is based primarily on the solubility of the polymer, ease of evaporation, and viscosity of the solution. In this present invention, mixture of water and isopropyl alcohol is preferred. In addition to coating materials, there are other excipients like binder, disintegrant, lubricant, surfactants, antifoaming agents, solubilizing agents, coloring agents etc.
Lubricant is selected from the one of stearic acid, glycerol, palmitate stearate, magnesium stearate, calcium stearate, talc, micropowder silica gel, hydrogenated vegetable oil, sodium lauryl sulphate. In this present invention, calcium stearate is used.
The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.
Example 1 : Production Methods
In the formulation, the reference product produced by Dr. Falk Pharma GmbH Salofalk® was referenced. The wet granulation production method, which is widely used in pharmaceutical technology, was preferred as the production method. Critical parameters at the production stage have been checked to optimize this selected production method. The excipients included in the composition are defined in international pharmacopoeias and their use in pharmaceutical products has been accepted. In the literature search, no incompatibility findings were found for the excipients used. Mesalazine 500 mg and 250 mg Enteric Coated Tablets have the same contents and proportions for used excipients due to the proportionality of dose.
During the formulation studies, due to dose proportionality, Mesalazine 250 mg Enteric Coated Tablet and Mesalazine 500 mg Enteric Coated Tablet obtained from the same granule were jointly evaluated in two steps: (i) Core Tablet Content and (ii) Enteric Coating Content.
A wet granulation of mesalazine active ingredient and excipients of microcrystalline cellulose, povidone, croscarmellose sodium and glycine, is prepared. The wet granules obtained are passed through a suitable sieve. The drying process is carried out in Fluid Bed Dryer. The required amount of sodium carbonate, colloidal silicon dioxide and calcium stearate are added to the granules obtained as a result of dry grinding and mixed. The blend is compressed into tablets to prepare tablet cores.
During the preparation of the core tablet, granules were prepared by wet granulation method, the amount of binder was changed by keeping the amount of water constant and the results were evaluated (FT01 and FT02). In the second stage, the formulation study was carried out by changing the amount of water used in wet granulation without changing the binder amount (FT02 and FT03).
Table 1 : Investigation of Binder Ratio and Water Content
Amount of Water in
Formulation Trial Binder Percent Result Granulation/ tablet
FT01 4% 390 mg/tablet Capping observed
No capping observed, but the
FT02 6% 390 mg/tablet dissolution rate was lower than the reference product in pH 7.2 medium.
Similar dissolution profiles
FT03 6% 200 mg/tablet were observed with the reference product. Appearance, dissolution studies and stability analyzes were considered in the evaluations made in the product development studies of the enteric coating stage. In terms of appearance, the coatings of the tablets should be uniform; the coating thickness should be evenly distributed over the tablet surface. Because homogeneous coating of qualified coatings such as enteric coating, controlled release coating in oval tablets is important in order to open the tablet at the desired pH. Likewise, attention should be paid to the uniformity of the round tablets in the coating process and to obtain the same thickness of coating all over the tablet.
Primarily, when starting the enteric coating, opadry containing coating with hypromellose and polyethylene glycol was coated on the tablet core so that the tablet surface was smooth and the enteric coating could be coated homogeneously on this surface. Coating can be achieved by using fluidized bed equipment and the solid unit dosage forms are coated by continuous spray methods. The film coating layer is applied onto the tablet cores with opadry containing solution.
Within the scope of enteric coating studies, the main purpose of using basic butylated methacrylate copolymer in the formulation is to prevent exposure to moisture during the stability of the core tablet, which is very suitable for moisture absorption. The main scope of using mixture of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1 is to to protect the tablet at pH values below 6 by allowing it to be released at pH values above pH 6. A first enteric coating layer is applied onto the film coated tablet core with a solution comprising basic butylated methacrylate copolymer, talc, triethyl citrate and isopropyl alcohol. A second enteric coating layer is applied onto the tablet having one enteric coating layer with a solution comprising mixture of poly(methacrylic acid, methyl methacrylate) 1:2 (A) and poly(methacrylic acid, methyl methacrylate) 1:1 (B), talc, triethyl citrate, yellow iron oxide, titanium dioxide and isopropyl alcohol. During the preparation of the second enteric coating, the rate of enteric coating polymers (A and B) was changed and the results were evaluated (FT04 - FT09). The final tablets are cured for 1 hour at 40-45°C. Example 2: In-Vitro Dissolution Studies
The finished mesalazine enteric coated tablets of present invention were compared with reference product Salofalk® to evaluate their performance in the USP Mesalamine Delayed Release Tablet - Performance tests.
USP Dissolution Test Specifications - Mesalamine Delayed-Release Tablets (USP Revision Bulletin Official May 1 , 2020)
Acid stage* 500 ml_ of 0.1 N hydrochloric acid
100 rpm, 37°C ±0.5 °C, 2 hours
Specification: Lower than 1% of the labeled amount of mesalazine dissolved
Buffer Stage 1** 900 mL of pH 6.0 phosphate buffer 100 rpm, 37°C ±0.5 °C, 1 hour Specification: Lower than 1% of the labeled amount of mesalazine dissolved
Buffer Stage 2 900 mL of pH 7.2 phosphate buffer
50 rpm, 37°C ±0.5 °C, 90 minutes
Specification: Not less than 80% (Q) of the labeled amount of mesalazine dissolved
* After 2 h of acid stage operation, withdraw an aliquot of the fluid, discard the remaining solution, and retain the Tablets in proper order so that each will be returned later to its respective vessel. Blot the Tablets with a paper towel to dry, and proceed immediately as directed in Buffer stage 1.
** After 1 h of buffer stage 1 , adjust the medium to a pH of 7.2 and proceed immediately to Buffer stage 2.
The content of the percentage of mesalazine (C7H7NO3) released in the test medium was determined by comparing the UV maximum absorbance at 302 nm for acid stage, at 330 nm for buffer stage 1 and at 332 nm for buffer stage 2.
The proposed USP tests for enteric tablets requires that the product withstand agitation (paddle at 100 rpm) in the artificial gastric fluid (0.1 N hydrochloric acid) at 37°C ±0.5°C, releasing less than 1% of the labeled amount of mesalazine for 2 hours and also the product withstand agitation (paddle at 100 rpm) in the pH 6.0 phosphate buffer at 37°C., releasing less than 1% of the labeled amount of mesalazine for 1 hour, while dissolving not less than 80% (Q) of the labeled amount of mesalazine in 90 minutes at 37°C with a buffer of pH 7.2.
In the preliminary experiments, the first enteric coating was applied with a solution comprising basic butylated methacrylate copolymer into the obtained film coated tablet core. In this study, 2%, 3% and 5% enteric coating studies were applied for analyzing the first enteric coating layer.
The drug release of the tablet was monitored in vitro by applying different rates of enteric coating in the first and second enteric coating stages (FT04 - FT09) and given at Table 3. Table 3: Comparison of formulations containing different amounts of enteric coating with USP Performance Test
Film coating First Second
Formulation Opadry based Enteric Enteric Result
Trial film coating Coating* Coating**
FT04 3% 2% A:B ratio 4:1 USP specifications provided
FT05 3% 2% A:B ratio 2:1 USP specifications provided
FT06 3% 3% A:B ratio 4:1 USP specifications provided
FT07 3% 3% A:B ratio 2:1 USP specifications provided
FT08 3% 5% A:B ratio 4:1 USP specifications provided
FT09 3% 5% A:B ratio 2:1 USP specifications provided
* Basic butylated methacrylate copolymer
**A: poly(methacrylic acid, methyl methacrylate) 1:2 B: poly(methacrylic acid, methyl methacrylate) 1:1
According to the studies conducted above, it was found that the tablets obtained as a result of the first enteric coating containing 2%, 3% and 5% basic butylated methacrylate copolymer on the film-coated tablet core and the second enteric coating in different proportions met the USP specifications at in-vitro dissolution tests. Among these studies, Test formulation FT07 was selected for use in other studies.
In the present invention, enteric coated tablets containing dose proportional 500 mg and 250 mg mesalazine were prepared with the final formula (FT07) obtained at the end of the above-mentioned formulation determination studies. The finished mesalazine enteric coated tablets of present invention (500mg and 250 mg) were compared with reference product Salofalk® (500mg and 250 mg) to evaluate their in vitro dissolution profiles provided in the USP Mesalamine Delayed Release Tablet performance test. Comparative dissolution tests were conducted based on the general dissolution test method. Dissolution testing measures the portion (%) of mesalazine that have been dissolved in the dissolution medium. Dissolution test was performed with USP Apparatus-ll (paddle) at acid stage and buffer stage. Acid stage is 500 ml_ of 0.1 N hydrochloric acid and 100 rpm for 2 hours. Buffer stage consists of two stages. Buffer stage 1 is 900 ml_ of pH 6.0 phosphate buffer and 100 rpm for 1 hour. Buffer stage 2 is 900 ml_ of pH 7.2 phosphate buffer and 50 rpm for 90 minutes. After 2 hours of acid stage, samples are taken for analysis and the tablets are taken from the medium in order and added to the medium prepared for Buffer stage 1 and proceed immediately to Buffer stage 1. After 1 hour, samples are taken for analysis again and remove a 50 ml_ aliquot with addition of 50 ml_ sodium hydroxide solution to each dissolution vessel in order to adjust to a pH of 7.2, and continue the run to Buffer stage 2. The above exemplified compositions comprising mesalazine were tested in vitro and they were compared with a commercial reference product. It is well-known that the more exact the gastro-intestinal segments are simulated in vitro, the better the predictions on the actual behavior of the dosage form in vivo.
Since the proposed USP tests for Mesalamine delayed released tablets requires that the product withstand agitation (paddle at 100 rpm) in the artificial gastric fluid (0.1 N hydrochloric acid) at 37 C., releasing less than 1% of the labeled amount of mesalazine for 2 hours and also the product withstand agitation (paddle at 100 rpm) in the pH 6.0 phosphate buffer at 37 C., releasing less than 1% of the labeled amount of mesalazine for 1 hour, release profiles of mesalazine from enteric-coated tablets performed in pH 7.2 phosphate buffer for 90 minutes with rotation at 100 rpm at 37°C followed by 0.1 N HCI and pH 6.0 medium is shown in Figure 1.
In order to demonstrate in vitro that the enteric coating will not open in the stomach, the percentage of labeled amount of mesalazine dissolved in acid stage and buffer stage 1 mediums should not exceed 1% at the end of the two hours. At the end of 90 minutes for the buffer stage 2, the percentage of labelled amount of mesalazine dissolved should be not less than 80% (Q) (USP, Mesalamine Delayed-Release Tablets, Performance Tests). This also provides release the active substance mesalazine selectively at the inflamed areas in the gastrointestinal tract. However, Salofalk® 250 mg Enteric Coated Tablet (L19010A, Dr. Falk Pharma GmbH) does not meet the dissolution specifications stated in USP performance test (especially for pH 6.0 dissolution test results). Comparative dissolution studies evaluating non-conformance with USP specifications are given Table 4 below. Table 4. Comparative dissolution data (n=12) of Salofalk® 250mg Enteric Coated Tablet (L19010A, Dr. Falk) and Salofalk® 500mg Enteric Coated Tablet (R18029A, Dr.
Falk) _
Release %
Formulation Specification (0,1 N HCI + pH 6,0 Phosphate Medium)
Salofalk® 250mg Enteric 0,1 N HCI : <1% Coated Tablet pH 6.0: <1% 0,1 N HCI : <%1 pH 6.0: >%1 (L19010A, Dr. Falk) pH 7.2: >80 Salofalk® 500mg Enteric 0,1 N HCI : <1%
0,1 N HCI : <%1 Coated Tablet pH 6.0: <1% pH 6.0: <%1 (R18029A, Dr. Falk) pH 7.2: >80 pH 7.2: >80 Two different batches of Salofalk® 250 mg Enteric Coated Tablet were analyzed for dissolution test. The release percent results of mesalazine in the pH 6.0 phosphate buffer medium at the end of 1 hour following 0.1 N HCI medium for 2 hours is given at Table 5 below. Table 5. Dissolution % values of Salofalk® 250 mg Enteric Coated Tablet (L19010A & L6D20463L, Dr. Falk Pharma GmbH) in the pH 6.0 Phosphate Buffer medium at the end of 1 hour following 0.1 N HCI medium for 2 hours
Salofalk® 250 mg Enteric Coated Tablet (L19010A, Dr. Falk Pharma GmbH)
Tablets
~m #2 #3 #4 #5 #6 #7 #8 #9 #10 #ϊΐ #12
%9 %1.1 %1.1 %1 .5 %0.36 %1.8 %2.1 %38.6 %19.3 %2.9 %0.7 %3.5
Salofalk® 250 mg Enteric Coated Tablet (L6D20463L, Dr. Falk Pharma GmbH)
Tablets
#1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #ϊϊ #12
%7.9 % 17.8 %1.1 %2.5 %13.2 %1.1 %3.4 %16.5 %0.9 %4.2 %8.4 %10.1
Applicants have found that reference product of Salofalk® 250 mg Enteric tablets do not pass the USP dissolution test for Mesalamine Delayed Release tablet products, whereas enteric coated tablet products obtained in the invention consistently pass this test. Example 3. Stability Studies
It is known that the successful treatment of the acute episode of ulcerative colitis as well as the prevention of recurrency with enteric coated tablets comprising mesalazine require a defined release profile of mesalazine from the dosage form. Since the criterion for stability of an enteric coated dosage form is that it should not release a significant amount of the active ingredient in the stomach, but should dissolve completely in the higher pH environment of the intestine, in vitro dissolution stability is monitored in 0.1 N hydrochloric acid, pH 6.0 phosphate buffer and pH 7.2 phosphate buffer. The USP standards for enteric coated tablets entails stability testing of the products at elevated temperatures for extended periods of time. The enteric tablets coated with multilayer enteric coating polymers prepared as per the Example 1 (FT07 - 500mg and 250mg Enteric Coated Tablet) were packed in PVC/PVDC-ALU blisters and and kept for stability testing together with reference products (Salofalk® 500mg and 250mg Enteric Coated Tablets) under conditions given as 40°C/75% relative humidity for 6 months and 25°C/60% relative humidity for 12 months duration.
The products were tested for content, purity and dissolution of mesalazine from enteric- coated tablets at acid and buffer medium conditions in regular intervals. Determination of content and purity was performed with a validated HPLC method at 254 nm. The determination of mesalazine release from enteric coated tablets was performed with a validated UV method at 302 nm for acid stage, at 330 nm for buffer stage 1 and at 332 nm for buffer stage 2.
In order to examine the physical and chemical stability of the products, stability test was assessed under accelerated condition (40°C±2°C, 75% Relative humidity, RH±5%) and ambient temperature condition (25°C±2°C / 60±5% Relative Humidity, RH±5%) for Test products (Example 1-FT07) and Reference Products (Salofalk®
500mg and 250mg Enteric Coated Tablets) according to ICH Stability Testing Of New Drug Substances And Products Q1A(R2) Guidelines. The stability results were summarized at Table 6 and Table 7. USP Specifications - Mesalamine Delayed-Release Tablets (USP Revision Bulletin Official May 1, 2020)
Assay- Mesalazine 90.0% - 110.0%
Purity Individual impurity: The largest secondary peak is NMT 1 .0% of the total area.
Any other individual impurity: NMT 0.5%
Total impurities: NMT 2.0%
Dissolution Test
Acid stage 500 mL of 0.1 N hydrochloric acid 100 rpm, 37°C ±0.5 °C, 2 hours
Specification: Lower than 1% dissolved
Buffer Stage 1 900 mL of pH 6.0 phosphate buffer 100 rpm, 37°C ±0.5 °C, 1 hour
Specification: Lower than 1% dissolved
Buffer Stage 2 900 mL of pH 7.2 phosphate buffer 50 rpm, 37°C ±0.5 °C, 90 minutes
Specification: Not less than 80% (Q) of the labeled amount of mesalamine dissolved
In accelerated and long term stability conditions tests, applicants have found that reference product of Salofalk® 250 g Enteric tablets do not pass the USP Dissolution Test for Mesalamine Delayed Release tablets, whereas obtained in the invention enteric coated tablet products consistently pass this USP test.
Table 6. Summarized stability results (n=6) of Mesalazine 500 mg and 250 mg Enteric Tablet (Example 1-FT07)
Test product (Example 1 - FT07)
Mesalazine 500mg Enteric Coated Tablet
6 months 12 months Table 7. Summarized stability results (n=6) of Reference Product (Salofalk® 500 mg and 250mg Enteric Coated Tablet)
Reference Product
Salofalk ® 500mg Enteric Coated Tablet
6 months 12 months
X: Not analyzed
Additionally, the in vitro dissolution results obtained in the pH 6.0 phosphate buffer medium at the end of 1 hour following 0.1 N HCI medium for 2 hours after specified stability conditions of the product Salofalk® 250 mg Enteric Coated Tablet are given in detail at Table 8.
Table 8. Dissolution % values of Salofalk® 250 mg Enteric Coated Tablet (L19010A, Dr. Falk Pharma GmbH) in the pH 6.0 Phosphate Buffer medium at the end of 1 hour following 0.1 N HCI medium for 2 hours after specified stability conditions
After 6 months
_ at 40°C/75% RH _
Tablets
#1 #2 #3 #4 #5 #6
65% 88.9% 92.5% 91.1% 91.1% 88.9%
After 12 months at 25°C/60% RH
Tablets
#1 #2 #3 #4 #5 #6
10.7% 22.1% 64.6% 21.8% 28.9% 46.8%

Claims

1. A stable pharmaceutical mesalazine enteric tablet formulation, the produced enteric tablet releases less than 1% of the labeled amount of mesalazine after 2 hours acid stage when measured using USP dissolution apparatus II (paddle), 100rpm, 500 mL of 0.1 N hydrochloric acid medium and less than 1% of the labeled amount of mesalazine after 1 hour buffer stage 1 when measured using USP dissolution apparatus II (paddle), 100 rpm, 900 mL of pH 6.0 phosphate buffer, wherein the core tablet contains multilayer enteric coating consisting of;
(i) the first enteric coating layer comprises basic butylated methacrylate copolymer with a ratio range of 20:1 to 65:1 active ingredient mesalazine to basic butylated methacrylate copolymer,
(ii) the second enteric coating layer covering the first enteric coating layer comprises mixture of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1.
2. The enteric tablet formulation as claimed in claim 1, wherein the second enteric coating layer covering the first enteric coating layer comprises mixture of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1 in a ratio of 1:2 to 1:4.
3. The enteric tablet formulation as claimed in claim 2, wherein the second enteric coating layer covering the first enteric coating layer comprises mixture of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1 in a ratio of 1:4.
4. The enteric tablet formulation as claimed in claim 1, wherein the core tablets are prepared by wet granulation.
5. The enteric tablet formulation as claimed in claim 1, wherein the said tablets comprise 500 mg mesalazine.
6. The enteric tablet formulation as claimed in claim 1, wherein the said tablets comprise 250 mg mesalazine.
7. The enteric tablet formulation as claimed in claim 1, wherein the said tablet provides a method for preparing a mesalazine enteric coated tablet comprising:
(i) granulating a composition comprising mesalazine, a pharmaceutically acceptable salt, or ester thereof, into mesalazine granulates; (ii) tabletting a core composition comprising the mesalazine granulates obtained in (i) to obtain a tablet core;
(iii) film coating the tablet core obtained in (ii) with an intermediate layer;
(iv) a first enteric coating the coated tablet obtained in (iii) with a solution comprising basic butylated methacrylate copolymer;
(v) a second enteric coating the enteric coated tablet obtained in (iv) with a solution comprising mixture of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1.
8. The enteric tablet as claimed in claim 7, wherein the mesalazine granulates are produced by granulating active substance with microcrystalline cellulose, povidone, croscarmellose sodium and glycine.
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EP2425826A1 (en) * 2010-09-01 2012-03-07 Disphar International B.V. Mesalazine tablet having improved dissolution
CN102048707A (en) * 2010-11-29 2011-05-11 黑龙江天宏药业有限公司 Mesalazine enteric-coated tablet and preparation method thereof
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